Dynamic Regulation of Vesicle Pools in a Detailed Spatial Model of the Complete Synaptic Vesicle Cycle

Synaptic transmission is driven by a complex cycle of synaptic vesicle docking, release, and recycling, and maintained by distinct vesicle pools with differing propensities for docking and release. However, the partitioning of vesicles into distinct pools and the conditions under which they are recruited from the reserve to the recycling pool remain poorly understood. Whilst computational modeling at the molecular level has progressed massively in recent years, modeling voluminous, dynamic, and heterogenous structures such as synaptic vesicles remains an unsolved problem. Here, we use a novel vesicle modeling technology to model the complete synaptic vesicle cycle in unprecedented molecular and spatial detail at a hippocampal en passant synapse, incorporating vesicle diffusion, the accumulation and diffusion of proteins on the vesicle surface, vesicle clustering, tethering, and docking, and regulated vesicle fusion and recycling. Our model demonstrates highly dynamic and robust recycling of synaptic vesicles able to maintain stable and consistent synaptic release over time, even during high frequency and sustained firing. We also reveal how the cytosolic proteins synapsin-1 and tomosyn-1 can cooperate to regulate the recruitment of vesicles from the reserve pool during sustained periods of synaptic activity in order to maintain transmission, as well as the potential of selective vesicle tethering close to the active zone to ensure rapid vesicle replenishment and enhance the efficiency of the vesicle cycle by minimizing the recruitment of vesicles from the reserve pool.